Mid-Life Plasmalogens and Other Metabolites with Anti-Inflammatory Properties are Inversely Associated with Long term Cardiovascular Disease Events: Heart SCORE Study

Background Preclinical data have shown that low levels of plasmalogens and other metabolites with anti-inflammatory properties may impact metabolic disease processes. However, the association between mid-life levels of such metabolites and late-life atherosclerotic cardiovascular disease (ASCVD) is not known. Methods We characterized the midlife plasma metabolomic profile (1,228 metabolites) of 1,852 participants (age 58.1±7.5 years, 69.6% female, 43.6% self-identified as Black) enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Participants were followed for ∼16 years for incident ASCVD events (nonfatal MI, acute ischemic syndrome, coronary revascularization and ASCVD mortality). We used regression model to assess associations of metabolites with ASCVD events. We assessed the impact of genetic variants using whole-exome sequencing with single-variant analysis for common variants and gene-based burden tests for rare variants. We used unbiased and candidate gene approaches to explore genetic associations with metabolites found to be associated with ASCVD events. Results A total of twelve metabolites were independently associated with incident ASCVD in fully adjusted models over a median of 12.1 years. A subset of plasmalogens showed an independent inverse association with incident ASCVD events [1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC (OR, 0.54; 95% CI, 0.40-0.74); 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE (OR, 0.57; 95% CI, 0.42-0.78), 1-methylnicotinamide1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (OR, 0.76; 95% CI, 0.65-0.89)]. Metabolome-wide genetic analysis revealed that two of these plasmalogen metabolites were strongly influenced by polymorphisms of the rs174535, an eQTL for FADS1 and FADS2 genotype. Two amino acid metabolites (2-oxoarginine [OR, 0.42; 95% CI, 0.25-0.69], alpha-ketobutyrate [OR, 0.62; 95% CI, 0.49-0.80]) and a bilirubin degradation product (C16H18N2O5 [OR, 0.50; 95% CI, 0.38-0.66) were inversely associated with ASCVD events. Conclusions Higher mid-life levels of three plasmalogens, two amino acid metabolites, and a bilirubin degradation product, all of which have anti-inflammatory properties, are associated with lower risk of late-life ASCVD events. Further research is needed to determine whether these metabolites play a causal role in ASCVD and may be a target for future therapies. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Pennsylvania Department of Health (ME-02-384). The department specifically disclaims responsibility for any analyses, interpretations, or conclusions. Additional funding was provided by National Institutes of Health grant R01HL089292. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB Approval need was waived. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors